The cerebellum is known to be concerned with smooth and effective control of motor movement. This role is well illustrated in animal models and human diseases: pathological changes in the cerebellum are known to produce ataxia, tremor and myoclonus. Recently diffuse serotonergic innervation throughout the cerebellum has been demonstrated. Serotonin agonists have been shown to modify DDT-myoclonus, harmaline-tremor and metrazol seizures as well as to alleviate certain types of intention myoclonus in patients. There is considerable evidence suggesting that cerebellar pathways are involved in the production of these movement disorders. Cerebellar cyclic GMP has been found to be elevated in these animal models. The objectives of the proposed research are to determine the effects of serotonin (1) on stimulus-induced release of cerebellar specific neurotransmitters and (2) norepinephrine and amino acid induced alteration of cerebellar cyclic GMP. We have found that 3-acetyl-pyridine (3-AP) pretreatment in rats, which deprives the cerebellum of its climbing fiber input (by destroying the inferior olive, I.O.) aggravates myoclonus induced by DDT and abolishes the antimyoclonic action of clonazepam and L-5-hydroxytryptophan, a precursor of serotonin. Loss of clonazepam's antimyoclonic action in 3-AP-treated rats was paralleled by loss of clonazepam's action of DDT-induced elevation of cerebellar cGMP. I propose to determine the specific role of serotonergic innervation of the I.O. in mediating these behavioral and biochemical changes. Other neurotransmitter input to the I.O. also may be relevant to these effects. I plan to identify the neurotransmitters released by the rubro-I.O., spino-I.O. and Deep Nuclei-I.O. projections. This goal will be accomplished by measuring neurotransmitter high affinity uptake and specific receptor binding in control and lesioned animals (ibotenic acid lesions of Red Nucleus, deep cerebellar nuclei, graclilis nuclei and 3-AP lesion of I.O.). The proposed research should define the functional effects of serotonergic innervation of the I.O. and cerebellum and elucidate its interaction with other neurotransmitter input to these regions.